Preparation of insect juvenile hormone (JH) antagonists and identification of JH receptors

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Ethyl 4-[2-(tert-butylcarbonyloxy)butyloxy]benzoate (ETB), an anti juvenile hormone (anti-JH) agent, has been reported to act as a partial JH antagonist at the target tissue of the larval epidermis. By modifying the structure of ETB, we have found that ethyl [2-(6-methyl-3-pyridyloxy)butyloxy]-benzoate (EMP) induced precocious metamorphosis in larvae of Bombyx mori, which is clearly recognized as a JH-deficiency symptom. In contrast to ETB, EMP induced precocious metamorphosis in a dose-dependent manner. The structure-activity relationship studies indicated that the 4-ethoxycarbonyl group on the benzene ring and the 6-methyl-3-pyridyl moiety were apparently essential for activity. The activity of EMP could be fully counteracted by methoprene, a JH agonist, but not by the dietary administration of 20-hydroxyecdysone, indicating that EMP causes a deficiency of JH titers in the larval hemolymph. In order to identify a target molecule of EMP, which might be related to a JH receptor, an EMP … More derivative coupled to horseradish peroxidase was prepared as an affinity ligand. However, high-affinity binding site for EMP was not found in the ovary follicular cell of the pupae and larval head capsules. To develop more potent anti-JH agent, the ethyl side chain of EMP was modified. Of the compounds tested, ethyl 4-[4-methyl-2-(6-methyl-3-pyridyloxy)pentyl-oxy]benzoate (1) was the most effective when applied to 24hr-old 3rd instar larvae. There was no significant different in precocious metamorphosis-inducing activity between 1R(+)- and 1S(-)-enantiomers. Since the benzoic acid analogs did not show any activity by both topical application and dietary administration, the ethoxycarbonyl group itself was responsible for activity. When 3rd instar larvae were treated with compound 1, hemolymph JH esterase, which is indispensable for the initiation of pupation in the last instar larvae, was induced during the 4th instar larvae. Compound 1 represents a structurally novel class of anti-JH agent. Less